WJ CC World Journal of

Clinical Cases
Submit a Manuscript: http://www.wjgnet.com/esps/ World J Clin Cases 2014 September 16; 2(9): 432-438
Help Desk: http://www.wjgnet.com/esps/helpdesk.aspx ISSN 2307-8960 (online)
DOI: 10.12998/wjcc.v2.i9.432 © 2014 Baishideng Publishing Group Inc. All rights reserved.

THERAPEUTICS ADVANCES

Targeting EGFR and sonic hedgehog pathways for locally

advanced eyelid and periocular carcinomas

Vivian T Yin, Helen Merritt, Bita Esmaeli

Vivian T Yin, Bita Esmaeli, Orbital Oncology and Ophthalmic ma; Sonic hedgehog; Epithelial growth factor receptor
Plastic Surgery Program, Department of Plastic Surgery, The inhibition; Periocular squamous cell carcinoma
University of Texas MD Anderson Cancer Center, Houston, TX
77030, United States Core tip: Targeted therapies provide a novel and poten-
Helen Merritt, Department of Ophthalmology and Visual Sci-
tially effective treatment alternative for patients with
ence, The University of Texas Medical School, Houston, TX
77030, United States eyelid carcinoma not amendable for surgery, including
Author contributions: Yin VT and Esmaeli B were involved in those with metastatic, locally advanced disease, ad-
the writing and editing of the manuscript; Merritt H co-ordinated vanced age, and significant comorbidities. High cost,
and provided writing and literature review. need for long-term treatment, and toxicity are relative
Correspondence to: Bita Esmaeli, MD, FACS, Orbital Oncol- limitations.
ogy and Ophthalmic Plastic Surgery, Department of Plastic Sur-
gery, The University of Texas MD Anderson Cancer Center, 1515
Holcombe Blvd, Unit 1488, Houston, TX 77030, Yin VT, Merritt H, Esmaeli B. Targeting EGFR and sonic hedge-
United States. [email protected]
hog pathways for locally advanced eyelid and periocular carci-
Telephone: +1-713-7924457 Fax: +1-713-5638041
Received: February 16, 2014 Revised: July 24, 2014 nomas. World J Clin Cases 2014; 2(9): 432-438 Available from:
Accepted: August 27, 2014 URL: http://www.wjgnet.com/2307-8960/full/v2/i9/432.htm
Published online: September 16, 2014 DOI: http://dx.doi.org/10.12998/wjcc.v2.i9.432

Abstract INTRODUCTION
For patients with metastatic or locally advanced eye- Eyelid malignancies have been reported with yearly inci-
lid and periocular carcinoma not amenable to surgical dence as high as 15.7 cases per 100000 individuals in the
excision, targeted therapies have shown efficacy with United States[1]. The most common type of eyelid carci-
better tolerability compared to cytotoxic chemotherapy. noma is basal cell carcinoma (BCC), accounting for 86%
Overexpression of epithelial growth factor receptor was to 96% of all cases, followed by squamous cell carcinoma
found in squamous cell carcinomas. Vismodegib tar- (SCC), 3.4% to 12.6%, sebaceous carcinoma (SebCa),
gets the mutation in the hedgehog pathway identified 0.6% to 10.2%, and melanoma, less than 1%[1-3]. Distant
in basal cell carcinoma and basal cell nevus syndrome. metastasis from eyelid carcinoma is not common, report-
Targeted therapies provide a novel and potentially ef-
ed in up to 6% of squamous cell carcinoma[4]. Further-
fective treatment alternative for patients with eyelid
more, the integrity of the eyelids are essential for protec-
carcinoma not amendable for surgery, including those
with metastatic, locally advanced disease, advanced
tion and function of the globe making locally advanced
age, and significant comorbidities. High cost, need for disease difficult if not impossible to resect completely
long-term treatment, and toxicity are relative limita- without disruption of globe function.
tions. Traditional cytotoxic chemotherapy for treatment of
metastatic or unresectable disease targets all rapidly divid-
© 2014 Baishideng Publishing Group Inc. All rights reserved. ing cells, whether cancerous or not. This results in an un-
favorable toxicity profile. With the discovery of the com-
Key words: Vismodegib; Periocular basal cell carcino- mon mutations in BCC and SCC, drug therapies targeted

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 Yin VT et al . Targeted therapy for periocular carcinoma

against these mutations can potentially block only the completely inhibits the activation of EGFR[13]. It is also
growth of cancer cells and thus lead to less wide spread able to induce dimerization of EGFR and down regula-
toxicity. In addition, many of these targeted therapies are tion and further activation by ligands[14]. In a phase 2
administered orally rather than by the intravenous route. study of 36 patients with unresectable (locally advanced
The ease of administration and lower toxicity generates or metastatic) SCC of the skin with confirmed strong or
momentous interest in these new classes of drugs. moderate expression of EGFR in the primary tumor, the
overall tumor response rate was 69% (95%CI: 52%-84%)
base on intent-to-treat and 81% (95%CI: 63%-93%) base
EGFR INHIBITION IN SQUAMOUS CELL on actual treatment received[15]. Cetuximab was given as
CARCINOMA an intravenous infusion at 400 mg/m2 dose followed by
weekly 1-hour infusion at a dose of 250 mg/m2. The
Epithelial growth factor receptor (EGFR), also known as
median number of infusion received during the 48-week
HER-1 or ErbB-1, is a transmembrane protein with an
study was 15 (range 1 to 47 infusions)[15]. There is cur-
extracellular receptor domain for multiple ligands, includ-
rently no published study on the effect of cetuximab
ing EGF, TGF-alpha and epiregulin, and an intracellular
compared to or in combination with standard cytotoxic
kinase domain with tyrosine autophosphorylation site[5]. chemotherapy. However, in a study of 424 head and neck
Upon activation, the EGFR forms homodimer with squamous cell carcinoma (HNSCC) randomized to high
another EGFR or heterodimer with another ErbB fam- dose radiation with or without cetuximab has shown
ily receptor. Multiple pathways can be activated by these superior median survival (54 mo vs 28 mo) with the addi-
dimer formations, including RAS/RAF/MEK/MAPK, tion of cetuximab[16].
PI3K/AKT and STAT. The resultant effect of EGFR Gefitinib (ZD1839, Iressa) was the first orally ad-
activation in both normal and malignant human skin is ministered EGFR inhibitor shown to selectively inhibit
severe epidermal disorganization and invasion[6]. EGFR tyrosine kinase activity through blockage of au-
Squamous cell carcinoma has been shown to have tophosphorylation[17]. Gefitinib was approved in 2003 as
overexpression of EGFR. In a series of 13 metastatic monotherapy for non-small cell lung cancer (NSCLC),
SCC of the skin, all showed strong expression of EGFR but the approval was amended to only in patients who
whereas normal skin close to the tumor had weak EGFR had previously benefited from the drug due to lack of
expression that was limited to the basal layer of the survival benefit especially when compared to erlotinib.
epidermis[7]. EGFR overexpression has been found in In vitro incubation of gefitinib with EGF and cutaneous
up to 78% (25 of 32) of cutaneous SCC cells and 62% SCC cells showed a dose-dependent reduction in EGFR
(13 of 21) of actinic keratoses (AKs)[8]. In conjunctival and MAPK phosphorylation between IC50 of 0.02 and
SCC, EGFR had either moderate or strong expression 0.2 μm[18]. In 22 patients with locally aggressive or recur-
of EGFR on all (5 out of 5) epithelial cell of conjunc- rent cutaneous SCC, neoadjuvant use of gefitinib 250 mg
tiva[9]. Furthermore, EGFR numerical aberration was per day showed overall response rate of 45.5% (95%CI:
found 77% (27 out of 35) SCC and 52% (13 out of 25) 24.4%-67.8%) and 2-year overall survival of 72.1%
of AKs[8]. Analysis of 3 lymph nodes of metastatic SCC (95%CI: 55.4%-93.9%)[19]. Of the 4 patients who showed
all showed amplification of 7p12-13, location of EGFR complete response in this study, all were alive and were
gene[10]. disease free at last follow-up[19]. In addition, 3 of these 4
EGFR expression level is also shown to be associated patients with complete response showed pathologic com-
with metastasis in 45 cases of head and neck SCC[11]. In plete response with no evidence of SCC in their resected
25 cases without metastasis, only 9 (36%) showed strong surgical tissue[19]. There is currently only 1 case report
expression for EGFR, compared to 11 of 14 cases (79%) of use of gefitinib as primary treatment for metastatic
with metastasis[11]. cutaneous SCC of the foot showed maintained clinical
response for 30 mo and an additional 12 mo with the ad-
dition of sirolimus[20].
EFFICACY OF EGFR INHIBITORS Erlotinib (OSI-744, Tarceva) is similar to gefitinib in
Cetuximab (C225, Erbitux) is a chimeric mouse-human that it inhibits EGFR activity through reduction of au-
IgG1 monoclonal antibody that primarily competitively tophosphorylation causing cell cycle arrest at G1 phase;
inhibits EGF binding at the same affinity as the natural however, it does this through competitive inhibition with
ligand[12]. It was approved for use by the Food and Drug ATP[21]. FDA first approved its use on November 18,
Administration (FDA) on March 1, 2006 for locally or 2004, for treatment of patients with locally advanced
regionally advanced head and neck cancer SCC (HN- or metastatic NSCLC after failure of at lease one prior
SCC) in combination with radiation therapy or as single chemotherapy regimen. It was later approved for use in
agent for recurrent or metastatic HNSCC after failing locally advanced or metastatic pancreatic carcinoma in
platinum-based therapy. It was the first EGFR inhibitor combination with gemcitabine and most recently as first-
studied in clinical trials and to be approved by FDA. In line therapy for metastatic NSCLC in the presence of
vivo study with A431 model epidermoid carcinoma cells EGFR mutation. To our knowledge the use of erlotinib
had shown that even in the presence of EGF, cetuximab in cutaneous SCC has only been investigated in one phase

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 Yin VT et al . Targeted therapy for periocular carcinoma

1 study of erlotinib plus radiation therapy after surgical

COST OF EGFR INHIBITORS
resection. The 2-year overall survival was 65% with me-
dian time to recurrence of 10.5mo (range 1 to 14 mo) in Cetuximab costs from $2.94 per milligram in Switzerland
the 15 Stage III cutaneous SCC patients included in this to $6.73 per milligram in the United States[32]. At the dos-
study[22]. Palliative treatment of metastatic cutaneous SCC age used in the phase 2 clinical trials, the cost would be
with erlotinib has been reported in multiple case reports approximately $28000/m2 or for an average white male
with initial tumor response[23-25]. In phase 2 studies of the cost of the course of cetuximab would be approxi-
locally advanced HNSCC, the addition of erlotinib to mately $37500. Cetuximab is approved in Europe and
cisplatin and 70Gy of radiation showed improved clinical Asia, specifically Japan, and available in central and south
response rate, 52% compared to 40%, however, this was America as well. In comparison, Iressa costs on average
not statistically significant, P = 0.08[26]. $79 per 250 mg tablet[33] and Tarceva cost on average $100
per 150 mg tablet[34], or cost of $2370 and $3000 per
month, respectively. Iressa and Tarceva are both available
USE OF EGFR INHIBITORS FOR ORBITAL in Europe and Asia in addition to the United States.
AND PERIORBITAL SCC
EGFR expression has been shown in 5 patients with con- PTCH1 GENE AND BASAL CELL
junctival SCC as moderate or strongly expressed in both
CARCINOMA
in situ and invasive components of SCC[9]. In contrast,
study of periocular sebaceous carcinoma showed lower Basal cell carcinoma (BCC) has been linked to disrup-
intensity of EGFR expression with only 2 (11%) of 19 tion in the Hedgehog (Hh) signaling cascade, a pathway
patients showing 3+ intensity of staining[27]. important during embryogenesis but normally inactive
Our group has also reported good clinical and ra- in the adult[35, 36]. Patched-1 (Ptch-1) is a transmembrane
diological tumor response to EGFR inhibitors in three receptor that normally has inhibitory effects on down-
patients who presented with locally advanced cutaneous stream receptor Smoothened (Smo)[37]. When Ptch-1 is
SCC of the periocular skin with orbital extension[25, 28]. activated, upon binding by Hh protein, the constitutive
Two of the three patients were treated with cetuximab at inhibition on Smo is reversed and produces angiogenesis
the standard dosage of 400 mg/m2 followed by 250 mg/ and cellular proliferation in tumorigenesis[38]. Specifically,
m2 weekly and the third was treated with erlotinib 150 mg expression of the downstream product GLI1 in basal
daily. One of the patients treated with cetuximab had in- cells is proposed to induce formation of BCC[39]. Muta-
volvement in the cavernous sinus, Meckel’s cave, trigemi- tions both in PTCH-1 and Smo have been identified in
nal tract and infraorbital nerve and showed improvement basal cell nevus syndrome and sporadic basal cell carcino-
in motility and sensation after 4 weeks of treatment. This mas[35,36,40,41]. Additionally, continued signaling of the Hh
patient’s tumor was also analyzed for 182 cancer-related pathway is needed for sustained growth of established
genes and found to have EGFR P753S mutation along BCCs in the mouse model[42].
with CDKN2A mutation, MYC amplication and TP53
mutation[28].
INHIBITION OF HEDGEHOG PATHWAY IN
SIDE EFFECTS OF EGFR INHIBITORS BCC
The most common side effect of EGFR inhibitors is Vismodegib (GDC-0449, Erivedge) is a first-in-class
skin toxicity in the form of an acne-like rash, papular small molecule oral Hh signaling pathway inhibitor ap-
and/or pustular follicular eruption, in 32% to 78% of proved January 2012 for the treatment of locally ad-
patient with a median time to onset of 14 d[7, 19]. Interest- vanced or metastatic BCC. Vismodegib directly binds to
ingly, the presence rash as a side effect during treatment and inhibits Smo[43]. Vismodegib’s inhibition at this point
was significantly correlated with higher overall response in the cascade prevents formation of GLI1 and there-
rate, median overall survival and progression-free sur- fore targets BCCs related to both constitutively activated
vival in patients treated with erlotinib for NSCLC[29]. Smo mutations and mutations in the upstream PTCH-1.
The lower incidence of acne-like rash with gefitinib is Hedgehog gene expression was reduced by 90% at 1
believed to be due to its attenuation instead of complete month after vismodegib treatment in in vivo studies[44].
blockage of EGFR tyrosine kinase. Instead, toxicity from Biopsy samples from patients treated with vismodegib
gefitinib is most commonly diarrhea and fatigue before showed decrease in GLI1 expression by more than two
rash[19]. Erlotinib is also associated with mucositis (87%), folds after treatment compared to baseline[45].
esophagitis (40%)[22], and ocular side effects including tri- At a dose of 150mg daily, vismodegib has shown
chomegaly leading to corneal ulceration[30], conjunctivitis no dose-limiting toxicities in Phase 1 trials[43,45,46]. Initial
and ectropion[31]. Discontinuation of EGFR inhibitors Phase I trial of 68 patients with advanced BCC and me-
due to toxicity varied from 9% with gefitinib[19], 11% in dulloblastoma compared doses of 150 mg/d to 270 mg/
cetuximab[7], and 13% in erlotinib[22]. d and 540 mg/d and demonstrated no increase in steady

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 Yin VT et al . Targeted therapy for periocular carcinoma

A B C

Figure 1 A 55 year-old man with locally advanced neglected basal cell carcinoma. A-B: The lesion involves the left lateral canthus, upper and lower eyelids, left
temple and midface; C: After 29 wk of vismodegib 150 mg daily, there is significant resolution of clinically visible tumor. The only surgical intervention that the patient
had undergone at this point was reconstructive surgery to repair the left lower lid cicatricial ectropion via a lateral tarsal strip procedure, a lateral tarsorrhaphy and full-
thickness skin graft.

state plasma concentrations associated with vismodegib cally eligible BCCs was noted even after cessation for sev-
efficacy with higher doses[43,45]. In the cohort of patients eral mo; 0.69 new lesions per month in the treated group
from the phase I trial, overall response was shown in compared to 2.4 per month in the placebo group.
18/33 patients (55%) with locally advanced or metastatic
BCC, 2/18 demonstrating complete response and 16/18
demonstrating partial response[45]. VISMODEGIB FOR ADVANCED
A phase 2 trial of 33 patients with metastatic BCC PERIOCULAR BCC
and 63 patients with locally advanced BCC also showed
The use of vismodegib specifically for periocular BCC
tumor response when given 150 mg of vismodegib daily
was first reported in a review by Yin et al [48] in which
for a mean duration of 10 mo[47]. Investigators found a
some of the patients treated with vismodegib in our
30% objective response rate in the group with metastatic
practice at MD Anderson Cancer Center were high-
basal-cell carcinoma as defined by a decrease of 30% or
more in the dimension or complete resolution of ulcer- lighted. In this report, a 30-year-old male patient with
ation. The overall objective response rate in the group advanced basal cell nevus syndrome and numerous large
with locally advanced BCC was 43% with 21% of these BCCs throughout his periocular and facial region includ-
patients demonstrating a complete response. By indepen- ing all four eyelids, experienced near complete resolution
dent review, none of patients in the metastatic cohort of his periocular lesions after 16 wk of treatment with
had complete response, 10 (30%) patients had partial durable response during the more than 2 years of follow-
response and disease progression was noted in 1 (3%) up. Subsequently Gill et al[49] highlighted the results of
patient with metastatic disease. vismodegib in 7 patients with advanced periocular or or-
Vismodegib has also demonstrated promise in treat- bital BCC for a mean duration of 11 wk. With the study’s
ment of basal-cell nevus syndrome. Tang et al[44] dem- mean follow-up duration of 7.3 mo, two out of seven pa-
onstrated reduction of existing BCC tumor burden and tients (29%) had complete regression, 2 out of 7 patients
prevention of new BCC in patients with basal-cell nevus (29%) had partial clinical regression greater than 80%,
syndrome. The vismodegib treatment group had a per- and 2 out of 7 patients had partial clinical regression less
patient average rate of 2 per year while the placebo group than 35%, and 1 patient progressed.
had a rate of 29 per patient per year. The investigators The histologic effects of vismodegib on a single case
also found a greater decrease (-65%) in the size of ex- of periocular BCC was demonstrated by Kahana et al[50]
isting basal cell carcinomas in the vismodegib group in a patient with recurrent orbital BCC. After 5 mo of
compared to the placebo group (-11%). There was no vismodegib, the patient opted for surgical excision due to
progression of tumors in the treatment group during vis- drug side effects. The surgical specimen showed lack of
modegib administration and no signs of resistance to the Ki-67 expression, a marker for proliferation, and mitotic
drug during the study. The response was so significant in index < 1%.
the treatment arm that the DSMB (Data Safety Monitor- The use of vismodegib in the periocular region can
ing Board) discontinued the study after the first interim yield impressive responses in patients with locally ad-
analysis. Biopsies sampled from sites of flat-appearing, vanced disease that would otherwise need major disfigur-
clinically-regressed basal cell lesions showed residual tu- ing surgery such as orbital exenteration or would experi-
mor in 1/6 samples (17%)[44]. Although discontinuation ence loss of major parts of their face during surgical
of vismodegib led to expected return of BCC at original resection. An example of impressive response in a recent
sites, significant decrease in the incidence of new surgi- such patient in our practice is shown in Figure 1.

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 Yin VT et al . Targeted therapy for periocular carcinoma

staging system: a medical center pathology based, 15-year

SIDE EFFECTS OF VISMODEGIB review. Clin Ophthalmol 2011; 5: 1645-1648 [PMID: 22140312
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Adverse reactions to vismodegib of any grade are report-
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The most common adverse events associated with vis- of literature. Am J Dermatopathol 2009; 31: 256-262 [PMID:
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6 Commandeur S, van Drongelen V, de Gruijl FR, El Ghal-
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